Association Of Several Single Nucleotide Polymorphisms Research Articles

Pain-related single nucleotide polymorphisms: association with lumbar spinal stenosis patient experience and non-surgical treatment outcomes.

Lumbar spinal stenosis (LSS) is common in our aging population resulting in pain and functional impairment. Recent advances in pain research have identified several single nucleotide polymorphisms (SNP) associated with inter-individual symptom and treatment response. The goal of the current study was to investigate the association of SNPs in Neuropeptide Y (NPY) and Catechol-O-methyltransferase (COMT) with pain, function, and treatment outcomes in Lumbar spinal stenosis (LSS) patients receiving non-surgical treatments. An exploratory observational biomarker study was performed ancillary to a previously published clinical trial evaluating three different non-surgical treatments for LSS. Saliva samples were obtained for single nucleotide polymorphism genotyping and blood samples were collected for NPY protein. Data on pain and function collected as part of the clinical trial at baseline, 2 and 6 months were examined for association with known polymorphisms in NPY and COMT. Subjects with the NPY rs16147 TT genotype exhibited higher baseline symptom severity but also a higher likelihood of responding to non-surgical treatments. Subjects with the COMT rs4680 GG genotype also exhibited higher baseline symptom severity but did not demonstrate greater response to treatment. NPY rs16147 and COMT rs4680 are important potential biomarkers associated with pain and function. NPY genotype may be useful in predicting response to non-surgical treatments in older adults with LSS.

The polygenic implication of clopidogrel responsiveness: Insights from platelet reactivity analysis and next-generation sequencing.

Clopidogrel is widely used worldwide as an antiplatelet therapy in patients with acute coronary disease. Genetic factors influence interindividual variability in response. Some studies have explored the polygenic contributions in the drug response, generating pharmacogenomic risk scores (PgxPRS). Importantly, these factors are less explored in underrepresented populations, such as Latin-American countries. Identifying patients at risk of high-on-treatment platelet reactivity (HTPR) is highly valuable in translational medicine. In this study we used a custom next-generation sequencing (NGS) panel composed of 91 single nucleotide polymorphisms (SNPs) and 28 genes related to clopidogrel metabolism, to analyze 70 patients with platelet reactivity values, assessed through closure time (CT). Our results demonstrated the association of SNPs with HTPR and non-HTPR, revealing the strongest associations with rs2286823 (OR: 5,0; 95% CI: 1,02-24,48; p: 0,03), rs2032582 (OR: 4,41; 95% CI: 1,20-16,12; p: 0,019), and rs1045642 (OR: 3,38; 95% CI: 0,96-11,9; p: 0,05). Bivariate regression analysis demonstrated the significant association of several SNPs with the CT value, a "surrogate" biomarker of clopidogrel response. Exploratory results from the LASSO regression model showed a high discriminatory capacity between HTPR and non-HTPR patients (AUC: 0,955), and the generated PgxPRS demonstrated a significant negative association between the risk score, CT value, and the condition of HTPR and non-HTPR. To our knowledge, our study addresses for the first time the analysis of the polygenic contribution in platelet reactivity using NGS and establishes PgxPRS derived from the LASSO model. Our results demonstrate the polygenic implication of clopidogrel response and offer insights applicable to the translational medicine of antiplatelet therapy in an understudied population.

Association of Paraoxonase-1 Genotype and Phenotype with Angiogram Positive Coronary Artery Disease.

ResumoFundamento Tem sido demonstrado que um aumento dos níveis séricos de PON1 é protetor contra vários distúrbios. Foi relatado que vários polimorfismos de nucleotídeo único (SNPs, single nucleotide polymorphisms ) do gene PON1 estão associados a níveis e atividade de proteínas enzimáticas séricas.Objetivos Investigar a associação de SNPs do PON1 e atividade da paraoxonase sérica com a doença arterial coronariana (DAC).Métodos Foram estudados 601 pacientes não relacionados submetidos à angiografia coronária, incluindo aqueles com estenose >50% (N=266) e aqueles com estenose <30% (N=335). Os SNPs rs662 e rs840560 do gene da paraoxonase foram determinados utilizando o método ARMS-PCR e o SNP rs705379 foi genotipado utilizando análise de PCR-RFLP. A atividade da paraoxonase sérica foi medida utilizando paraoxon como substrato. O valor de p<0,05 foi considerado significante.Resultados A atividade da paraoxonase sérica não foi significativamente diferente entre os grupos de estudo. Após ajuste para idade, sexo, hipertensão, diabetes mellitus e dislipidemia, o genótipo GG e o modelo codominante de rs662 foram positivamente associados a uma angiografia positiva (respectivamente, OR = 2,424, IC 95% [1,123-5,233], p <0,05, OR = 1,663, IC 95% [1,086-2,547]). A atividade da paraoxonase sérica foi significativamente maior no alelo G e variante GG do polimorfismo rs662, alelo A e variante AA de rs854560 e alelo C e variante CC de rs705379. A análise de haplótipos mostrou que o haplótipo ATC foi significativamente mais prevalente no grupo com angiografia negativa. A análise entre os grupos indicou que o alelo A de rs662 foi significativamente associado à menor atividade da paraoxonase no grupo com angiografia positiva (p=0,019).Conclusões A presença do alelo G do polimorfismo de nucleotídeo único rs662 está independentemente associada ao aumento do risco de DAC.

Interaction Between Methylenetetrahydrofolate Reductase (MTHFR) Gene Polymorphisms and Environment with Susceptibility to Ischemic Stroke in Chinese Population.

Aims:To investigate the association of several single-nucleotide polymorphisms (SNPs) within methylenetetrahydrofolate reductase (MTHFR) gene, and additional gene–environment interaction with ischemic stroke (IS) risk.Methods:Testing for Hardy–Weinberg equilibrium in controls was conducted using SNPstats (online software: http://bioinfo.iconcologia.net/SNPstats). Generalized multifactor dimensionality reduction (GMDR) was used to screen the best interaction combination among four SNPs within MTHFR gene and smoking or alcohol drinking.Results:The frequency of the rs4846049-A allele was 28.6% in IS patients and 19.1% in normal controls, in addition, the frequency of the rs3737967-T allele was 27.9% in IS patients and 20.3% in normal controls, which was also indicating a statistically significant difference. The rs4846049-A and rs3737967-T were associated with an increased risk of IS risk; adjusted odds ratios (ORs) (95% confidence interval [CI]) were 1.76 (1.28–2.13) and 1.51 (1.13–1.97), respectively. GMDR model found significant gene–alcohol drinking interaction combination, but no significant gene–tobacco smoking interaction combinations. In order to obtain the odds ratios and 95% CI for the joint effects of gene–alcohol drinking on IS, we conducted stratified analysis for interaction effect using logistic regression. We found that alcohol drinkers with rs4846049-CA/AA genotype also have the highest IS risk, compared with never drinkers with rs4846049-CC genotype, OR (95% CI) = 3.12 (1.83–4.45), after adjustment for age, smoke, and smoking status.Conclusions:The rs4846049-A and rs3737967-T, gene–environment interaction between rs1764391 and rs918592, gene–environment interaction between rs4846049 and alcohol drinking were all associated with increased IS risk.

TCF7L2 polymorphisms are associated with amygdalar volume in elderly individuals with Type 2 Diabetes

The association between several Single Nucleotide Polymorphisms (SNPs) within the transcription factor 7-like 2 (TCF7L2) gene and Type 2 Diabetes (T2D) as well as additional T2D-related traits is well established. Since alteration in total and regional brain volumes are consistent findings among T2D individuals, we studied the association of four T2D susceptibility SNPS within TCF7L2 (rs7901695, rs7903146, rs11196205, and rs12255372) with volumes of white matter hyperintensities (WMH), gray matter, and regional volumes of amygdala and hippocampus obtained from structural MRI among 191 T2D elderly Jewish individuals. Under recessive genetic model (controlling for age, sex and intracranial volume), we found that for all four SNPs, carriers of two copies of the T2D risk allele (homozygous genotype) had significantly smaller amygdalar volume: rs7901695- CC genotype vs. CT + TT genotypes, p = 0.002; rs7903146-TT vs. TC + CC, p = 0.003; rs11196205- CC vs. CG + GG, p = 0.0003; and rs12255372- TT vs. TG + GG, p = 0.003. Adjusting also for T2D-related covariates, body mass index (BMI), and ancestry did not change the results substantively (rs7901695, p = 0.003; rs7903146, p = 0.005; rs11196205, p = 0.001; and rs12255372, p = 0.005). Conditional analysis demonstrated that only rs11196205 was independently associated with amygdalar volume at a significant level. Separate analysis of left and right amygdala revealed stronger results for left amygdalar volume. Taken together, we report association of TCF7L2 SNPs with amygdalar volume among T2D elderly Jewish patients. Further studies in other populations are required to support these findings and reach more definitive conclusions.

Single nucleotide polymorphisms in transcription factor genes associated with susceptibility to oral cancer.

Oral cancer is a major public health concern in the Asian countries predominated by India which accounts for 33.81% of the annual global oral cancer burden. The well-established high-risk factors associated with oral cancer include tobacco, areca nut, alcohol consumption, and high-risk human papilloma virus types 16/18. Additionally, in the past two decades, the critical role of the genomic constitution of individuals in oral cancer susceptibility has emerged. Accumulating evidence indicates the association of several single nucleotide polymorphisms (SNPs) with oral cancer risk. Thus in the current study, we assessed the association of thirteen SNPs in seven transcription factor genes along with HBB (a control SNP) to identify high-risk genotypes associated with increased oral cancer risk in an Indian cohort of tobacco habitués. Fourteen SNPs were investigated in 500 patients with oral cancer and 500 clinically healthy long-term tobacco users as controls of Indian ethnicity. Allelic discrimination real-time polymerase chain reaction was the method of choice for genotyping the samples. Logistic regression analysis was performed and the association of SNPs with oral cancer risk was estimated using odds ratio (OR) and 95% confidence interval (CI). We observed five SNPs-rs2051526 (ETV6), rs6021247 (NFATC2), rs3757769 (SND1), rs7085532 (TCF7L2), and rs7778413 (SND1) indicating increased oral cancer risk with OR ranging from 1.61 to 34.60. Further, as a proof of concept, the coinheritance of high-risk genotypes in rs6021247 (NFATC2) GG (OR, 2.77; CI, 2.09-3.69) and rs7778413 (SND1) CC (OR, 34.60; CI, 17.32-69.13) reflected further increase in the risk with OR-49.94 (CI, 16.25-153.48). The present study indicates the association of transcription factor SNPs with increased oral cancer risk constituting "predictive biomarkers" in oral cancers.

Associations of IDUA and PTCH1 with Bone Mineral Density, Bone Turnover Markers, and Fractures in Chinese Elderly Patients with Osteoporosis.

Introduction Osteoporosis (OP) is a common polygenic disorder in the aging population, and several single nucleotide polymorphisms (SNPs) in the alpha-L-iduronidase (IDUA) gene and patched homolog 1 (PTCH1) gene regulate bone metabolism and affect bone mass. The study aimed at investigating the relationships of rs3755955 and rs6831280 in the IDUA gene and rs28377268 in the PTCH1 gene with bone mineral density (BMD), bone turnover markers (BTMs), and fractures in the elderly Chinese subjects with OP. Materials and Methods A cohort of 328 unrelated senile osteoporosis (SOP) patients with or without osteoporotic fractures was recruited. rs3755955, rs6831280, and rs28377268 polymorphisms were identified using SNaPshot technology. BTM levels were determined by electrochemiluminescence (ECL). Bone mineral densities (BMDs) at the lumbar spine (LS) and proximal femur sites were measured by dual-energy X-ray absorptiometry (DEXA) in all subjects. The Hardy-Weinberg equilibrium (HWE) test was performed. HWE P values and comparisons of genotype frequencies were estimated using the chi-square test. Analysis of covariance (ANCOVA) adjusted for confounding factors was performed to investigate associations of SNPs with BMDs and BTMs in subgroups. Results The chi-square test indicated that genotype distributions in the control group conformed to HWE (P > 0.05). The distributions of allele and genotype frequencies of rs6831280 between fracture and osteoporotic participants were significantly different (P-allele = 0.002 and P-genotype = 0.012, respectively). Concerning rs6831280, ANCOVA found BMDs at LS 2-4 (L2-4) and total hip (TH) among the study subjects suffering from SOP with GA genotype were lower than in those carrying GG or AA (P-L2-4 = 0.004 and P-TH = 0.027, respectively). Conclusions IDUA rs6831280 is associated with BMDs at L2-4 and TH in the elderly Chinese population with SOP and may serve as a marker for the genetic susceptibility to osteoporotic fractures.

The p.R47H Variant of TREM2 Gene is Associated With Late-onset Alzheimer Disease in Colombian Population.

We evaluated the association of several single-nucleotide polymorphisms in the triggering receptor expressed on myeloid cells 2 (TREM2) gene in a Colombian sample of late-onset Alzheimer disease (LOAD). The p.Q33* (rs104894002), p.R47H (rs75932628), p.R62H (rs143332484), and p.D87N (rs142232675) variants of TREM2 gene were directly genotyped using KASPar technology in 358 cases and 329 healthy controls. Sanger sequencing was used to validate >10% of KASPar's results. The Fisher exact test was used to compare the distribution of allelic and genotype frequency between cases and controls, and the Bonferroni correction was set at P<0.05. The minor allele frequency of rs75932628-T was 0.009 in cases and was not found in any healthy controls which suggests a significant association between rs75932628-T and LOAD risk in our sample (P=0.010). The rs143332484-T variant did not exhibit a significant association (P=0.160), whereas rs104894002 and rs142232675 were not found. Our findings suggest that the rs75932628-T variant of TREM2 is an important risk factor for LOAD in the Colombian population.

GT-repeat extension in the IL11 promoter is associated with Hirschsprung's disease (HSCR)

Hirschsprung's disease (HSCR) is a congenital disease characterized by intestinal obstruction due to a defective intestinal neural system. Frequently, the disease is associated with an intestinal inflammation. The most common known underlying genetic alterations are in the RET gene but HSCR can also be caused by mutations in other genes that are responsible for the maturation and migration of intestinal neural cells. Recently, a study in an Asian population reported a significant association of several single nucleotide polymorphisms (SNPs) in the IL11 (interleukin 11) gene with HSCR. We further explored the possible association of genetic alterations in the IL11 gene with HSCR and HSCR subtypes in an unrelated Caucasian population. We used a targeted sequencing approach to identify a total of 32 SNPs covering the coding region of the IL11 gene including the proximal part of the promoter and relevant SNPs described in the previous study. Genotype frequencies were compared using additive genetic models in 103 HSCR patients and 128 healthy controls. We failed to observe any significant association of SNPs with HSCR. However, there was a suggestive evidence for an association of the length of a dinucleotide repeat in the IL11 promoter region with HSCR with an over-representation of >7 GT repeat subtypes (OR = 4.982 (1.448–17.040), p-value = 0.0111) in HSCR patients. A similar trend was further observed in a subgroup of patients with long-segment HSCR (L-HSCR). These findings need to be replicated in a well-powered study. Changes in IL11 expression may be a link to the intestinal inflammation frequently observed in patients with HSCR.

Specific association of the rs6500265 and rs9933632 single-nucleotide polymorphisms in Japanese patients with antipyretic analgesic-related Stevens-Johnson syndrome and toxic epidermal necrolysis with severe ocular involvements.

A recent study using the microarray for single-nucleotide polymorphisms (SNPs) genotyping specifically designed for the Japanese population in combination with genome-wide imputation showed the association of several SNPs with cold medicine-related Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) with severe ocular complications. However, it remains to be determined whether these polymorphisms are associated with the onset of antipyretic analgesic (AA)-related SJS/TEN, the progression of severe ocular involvements (SOIs), or both AA-related SJS/TEN and SOI phenotypes. To gain a better understanding of the features of these genetic markers, we compared the allele and carrier frequencies of these SNPs among our original SJS/TEN patient groups: (a) AA-related SJS/TEN with SOIs, (b) AA-related SJS/TEN without SOIs, and (c) AA-unrelated SJS/TEN with SOIs. AA-related SJS/TEN with SOIs were found to be associated significantly with both rs6500265 [allele frequency: odds ratio (OR): 2.18; 95% confidence interval (CI): 1.30-3.65; P=0.0052; carrier frequency: OR: 2.52; 95% CI: 1.33-4.78; P=0.058] and rs9933632 (allele frequency: OR: 2.28: 95% CI: 1.37-3.79; P=0.0032; carrier frequency: OR: 2.76; 95% CI: 1.46-5.22; P=0.0031). In contrast, allele and carrier frequencies of these SNPs in patients with AA-related SJS/TEN without SOIs or with SOIs not treated with any AAs were comparable with those in healthy Japanese controls. Collectively, our findings indicate that the rs6500265 and rs9933632 SNPs could be specific markers for AA-related SJS/TEN with SOIs, suggesting that certain genetic backgrounds contribute toward the etiology of this complex syndrome.

Interactions between vitamin D receptor (VDR) gene and Interleukin-6 gene and environment factors on coronary heart disease risk in a Chinese Han population.

AimsTo investigate the association of several single nucleotide polymorphisms (SNPs) within Interleukin-6 (IL- 6) and vitamin D receptor (VDR) gene, and additional gene- gene and gene- smoking interaction with coronary heart disease (CHD) risk in a Chinese population.MethodsHardy-Weinberg equilibrium (HWE) examination was used by SNPstats (http://bioinfo.iconcologia.net/SNPstats). Generalized multifactor dimensionality reduction (GMDR) was used to screen the best interaction combination among SNPs and smoking. Stratified analysis for gene- smoking interaction was investigated by logistic regression.ResultsCHD risk was significantly higher in carriers with the C allele of rs1800796 within IL-6 gene than those with GG genotype (GC+ CC versus GG), adjusted OR (95%CI) =1.62 (1.19-2.23); CHD risk was also higher in carriers with the T allele of rs2228570 within VDR gene than those with CC genotype (CT+ TT versus CC), adjusted OR (95%CI) = 1.68 (1.26-2.17). However, we did not find any direct associations of the others SNPs in IL- 6 and VDR gene with CHD risk. We also found a significant interaction between rs1800796 and smoking, the cross-validation consistency of this two- locus model was 10/ 10, and the testing accuracy was 60.11%. Current smokers with rs1800796- GC or CC genotype have the highest CHD risk, compared to never- smokers with rs1800796- GG genotype within IL- 6 gene, OR (95%CI) = 2.57 (1.74 -3.46).ConclusionsWe found that the C allele of rs1800796 within IL-6 and T allele of rs2228570 within VDR gene, interaction between rs1800796 and smoking were all associated with increased CHD risk.

Genes Involved in Neurodevelopment, Neuroplasticity, and Bipolar Disorder: CACNA1C, CHRNA1, and MAPK1

Background: Bipolar disorder (BPD) is a common and severe mental disorder. The involvement of genetic factors in the pathophysiology of BPD is well known. In the present study, we tested the association of several single-nucleotide polymorphisms (SNPs) within 3 strong candidate genes (CACNA1C, CHRNA7, and MAPK1) with BPD. These genes are involved in monoamine-related pathways, as well as in dendrite development, neuronal survival, synaptic plasticity, and memory/learning. Methods: One hundred and thirty-two subjects diagnosed with BPD and 326 healthy controls of Korean ancestry were genotyped for 40 SNPs within CACNA1C, CHRNA17, and MAPK1. Distribution of alleles and block of haplotypes within each gene were compared in cases and controls. Interactions between variants in different loci were also tested. Results: Significant differences in the distribution of alleles between the cases and controls were detected for rs1016388 within CACNA1C, rs1514250, rs2337980, rs6494223, rs3826029 and rs4779565 within CHRNA7, and rs8136867 within MAPK1. Haplotype analyses also confirmed an involvement of variations within these genes in BPD. Finally, exploratory epistatic analyses demonstrated potential interactive effects, especially regarding variations in CACNA1C and CHRNA7. Limitations: Limited sample size and risk of false-positive findings. Discussion: Our data suggest a possible role of these 3 genes in BPD. Alterations of 1 or more common brain pathways (e.g., neurodevelopment and neuroplasticity, calcium signaling) may explain the obtained results.

Association of toll-like receptor gene polymorphisms and its interaction with HPV infection in determining the susceptibility of cervical cancer in Chinese Han population.

The aim of the study is to investigate the association of several single-nucleotide polymorphisms (SNPs) within Toll-like receptors (TLRs) gene and additional gene-gene and gene-human papillomavirus (HPV) infection interaction with cervical cancer risk. A total of 1262 participants are selected, including 420 cervical cancer patients and 842 control participants. Generalized multifactor dimensionality reduction (GMDR) was used to screen the best interaction combination among five SNPs within TLR gene and HPV infection. Logistic regression was performed to calculate the ORs (95 %CI) for association of five SNPs within TLR gene and additional gene-HPV infection interaction with cervical cancer risk. Cervical cancer risk was significantly higher in carriers of the T allele of rs3775290 within TLR2 gene, the G allele of rs7873784 within TLR4 gene, and the A allele of rs352140 within TLR9 gene than those with wild genotype; adjusted ORs (95 %CI) were 1.78 (1.20-2.24), 1.65 (1.23-2.12), and 1.70 (1.16-2.31). However, we did not find any significant association of rs4986791 and rs11536889 with cervical cancer risk. GMDR analysis suggested a significant two-locus model (p = 0.0107) involving rs352140 and HPV infection. Subjects with HPV infection and rs352140-GA + AA genotype within TLR9 gene have the highest cervical cancer risk, compared to no HPV infection participants with rs352140-GG genotype, OR (95 %CI) = 3.22 (1.68-4.81). Pairwise LD analysis did not find any significant haplotype combination associated with cervical cancer risk. The minor alleles of TLR2-rs3775290, TLR4-rs7873784, and TLR9-rs352140, and interaction between rs352140 and HPV infection were all associated with increased cervical cancer risk.

Association Analysis of Polymorphisms in TOMM40, CR1, PVRL2, SORL1, PICALM, and 14q32.13 Regions in Colombian Alzheimer Disease Patients.

We evaluated the association of several single-nucleotide polymorphisms in different genes including APOE, TOMM40, CR1, PVRL2, SORL1, PICALM, and GWA_14q32.13 in a Colombian sample of Late-Onset Alzheimer disease (LOAD) patients. A case-control study was conducted in 362 individuals (181 LOADs and 181 controls) to determine the association of single-nucleotide polymorphisms in APOE (e2, e3, and e4), TOMM40 (rs2075650), CR1 (rs665640), PVRL2 (rs6859), SORL1 (rs11218304), PICALM (rs3851179), and GWA_14q32.13 (rs11622883) with LOAD in a sample from Colombia. We were able to confirm the previously reported association of the APOE4 allele with AD. In addition, we report a new significant association with rs2075650 of TOMM40 for LOAD in our sample. We did not detect any significant interaction between TOMM40 and APOE4 carriers (heterozygous or homozygous) for disease risk development. However, Kaplan-Meier survival analyses suggest that AD patients with TOMM40 allele rs2075650-G have an average age of disease onset of 6 years earlier compared with carriers of the A allele. In addition, the age of disease onset is earlier if APOE4/4 is present. Our findings suggest that rs2075650 of TOMM40 could be involved in earlier presentation of LOAD in the Colombian population.

ORMDL3 expression levels have no influence on the activity of serine palmitoyltransferase.

ORMDL proteins are believed to be negative regulators of serine palmitoyltransferase (SPT), which catalyzes the first and rate limiting step in sphingolipid (SL) de novo synthesis. Several single-nucleotide polymorphisms (SNPs) that are close to the ORMDL3 locus have been reported to increase ORMDL3 expression and to be associated with an elevated risk for early childhood asthma; however, the direct effect of ORMDL3 expression on SPT activity and its link to asthma remains elusive. In this study, we investigated whether ORMDL3 expression is associated with changes in SPT activity and total SL levels. Ormdl3-knockout (Ormdl3-/-) and transgenic (Ormdl3Tg/wt) mice were generated to study the effect of ORMDL3 on total SL levels in plasma and tissues. Cellular SPT activity was measured in mouse embryonic fibroblasts from Ormdl3-/- mice, as well as in HEK293 cells in which ORMDL3 was overexpressed and silenced. Furthermore, we analyzed the association of the reported ORMDL3 asthma SNPs with plasma sphingoid bases in a population-based cohort of 971 individuals. Total C18-long chain bases were not significantly altered in the plasma and tissues of Ormdl3-/- mice, whereas C18-sphinganine showed a small and significant increase in plasma, lung, and liver tissues. Mouse embryonic fibroblast cells from Ormdl3-/- mice did not show an altered SPT activity compared with Ormdl3+/- and Ormdl3+/+ mice. Overexpression or knockdown of ORMDL3 in HEK293 cells did not alter SPT activity; however, parallel knockdown of all 3 ORMDL isoforms increased enzyme activity significantly. A significant association of the annotated ORMDL3 asthma SNPs with plasma long-chain sphingoid base levels could not be confirmed. ORMDL3 expression levels seem not to be directly associated with changes in SPT activity. ORMDL3 might influence de novo sphingolipid metabolism downstream of SPT.-Zhakupova, A., Debeuf, N., Krols, M., Toussaint, W., Vanhoutte, L., Alecu, I., Kutalik, Z., Vollenweider, P., Ernst, D., von Eckardstein, A., Lambrecht, B. N., Janssens, S., Hornemann, T. ORMDL3 expression levels have no influence on the activity of serine palmitoyltransferase.

Low-Dose Aspirin-Associated Upper and Mid Gastrointestinal Tract Damage and Gene Polymorphism

The risk of gastrointestinal (GI) bleeding is increased in association with the use of low-dose aspirin (LDA). There are few studies of the association between genetic polymorphisms and the risks of aspirin-induced ulcer or its complications. Individuals with two single nucleotide polymorphisms (SNPs) of cyclooxygenase-1 (COX-1), A-842G and C50T, exhibit increased sensitivity to aspirin and lower prostaglandin synthesis capacity but the polymorphism lacked statistical significance in relation to an association with bleeding peptic ulcer. In our previous Japanese study, SLCO1B1 521TT genotype and the SLCO1B1 *1b haplotype were significantly associated with the risk of peptic ulcer and ulcer bleeding in patients taking LDA, especially in the patients with angiotensin converting enzyme inhibitor (ACEI), angiotensin type 1 receptor blocker (ARB), or statin co-treatment. Protonpump inhibitors (PPIs) are recommended for patients who require antiplatelet therapy and have a history of upper GI bleeding. The interaction between PPIs and consequent impaired effectiveness of clopidogrel has caused concern regarding the effect of genetic polymorphisms of the CYP2C19 which mediates conversion of clopidogrel to its active metabolite. The later recent genome-wide analysis of SNPs indicated the association of several SNPs with small bowel bleeding in Japanese patients taking LDA. The data are still lacking and further prospective studies are needed to identify the specific gene polymorphisms as risk or protective factors for GI bleeding associated with LDA.

Expression quantitative trait loci for TNFRSF10 influence both HBV infection and hepatocellular carcinoma development.

Tumor necrosis factor receptor superfamily member 10 (TNFRSF10) is a death domain-containing receptor for the apoptotic ligand TNFSF10, which involves multiple processes, including hepatocarcinogenesis and immune response against HBV infection. Several single nucleotide polymorphisms (SNPs) were identified as expression quantitative trait loci (eQTLs) for TNFRSF10. To assess the association of TNFRSF10 eQTL SNPs with the risk of hepatocellular carcinoma (HCC) and chronic HBV infection, we designed a case-control study that included 1,300 HBV-related HCC patients, 1,344 chronic HBV carriers, and 1,344 subjects with HBV natural clearance, and then genotyped two TNFRSF10 eQTL SNPs (rs79037040 and rs2055822). We found that rs79037040 GT/TT genotypes were associated with a decreased HCC risk (adjusted odds ratio [OR] = 0.83, 95% confidence intervals [CIs] = 0.71-0.97, P = 0.021) but an increased chronic HBV infection risk of borderline significance (adjusted OR = 1.14, 95%CIs = 0.98-1.33, P = 0.085). In contrast, the rs2055822 G allele was a risk factor for HCC (adjusted OR = 1.12, 95%CIs = 1.00-1.25, P = 0.041) but a protective factor for chronic HBV infection (adjusted OR = 0.89, 95%CIs = 0.80-0.99, P = 0.038). Furthermore, we observed a dose-dependent relationship between the number of alleles (rs79037040-T and rs2055822-A) and the risk of HCC and chronic HBV infection. In comparison with "0" alleles, having "1-4" alleles was significantly associated with decreased HCC risk and increased HBV infection risk. These findings suggest that eQTL SNPs for TNFRSF10 may be susceptibility markers for HCC and chronic HBV infection.

Circulating vitamin D, vitamin D-related genetic variation, and risk of fatal prostate cancer in the National Cancer Institute Breast and Prostate Cancer Cohort Consortium.

Evidence from experimental animal and cell line studies supports a beneficial role for vitamin D in prostate cancer (PCa). Although the results from human studies have been mainly null for overall PCa risk, there may be a benefit for survival. This study assessed the associations of circulating 25-hydroxyvitamin D (25(OH)D) and common variations in key vitamin D-related genes with fatal PCa. In a large cohort consortium, 518 fatal cases and 2986 controls with 25(OH)D data were identified. Genotyping information for 91 single-nucleotide polymorphisms (SNPs) in 7 vitamin D-related genes (vitamin D receptor, group-specific component, cytochrome P450 27A1 [CYP27A1], CYP27B1, CYP24A1, CYP2R1, and retinoid X receptor α) was available for 496 fatal cases and 3577 controls. Unconditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the associations of 25(OH)D and SNPs with fatal PCa. The study also tested for 25(OH)D-SNP interactions among 264 fatal cases and 1169 controls. No statistically significant relationship was observed between 25(OH)D and fatal PCa (OR for extreme quartiles, 0.86; 95% CI, 0.65-1.14; P for trend = .22) or the main effects of the SNPs and fatal PCa. There was evidence suggesting that associations of several SNPs, including 5 related to circulating 25(OH)D, with fatal PCa were modified by 25(OH)D. Individually, these associations did not remain significant after multiple testing; however, the P value for the set-based test for CYP2R1 was .002. Statistically significant associations were not observed for either 25(OH)D or vitamin D-related SNPs with fatal PCa. The effect modification of 25(OH)D associations by biologically plausible genetic variation may deserve further exploration.

Glutathione Peroxidase 3 Serum Levels and GPX3 Gene Polymorphisms in Subjects with Metabolic Syndrome

Glutathione peroxidase 3 (GPx3) plays a main role in removing hydro- and lipoperoxides from the body. Changes in concentration and several single-nucleotide polymorphisms (SNP) at the GPX3 gene have been associated with vascular diseases, but the relationship of GPx3 with metabolic syndrome (MetS) remains unexplored. We undertook this study to determine the association of GPx3 serum levels and several GPX3 SNPs with the presence of MetS in Mexican subjects. Clinical, biochemical, and anthropometric evaluation were conducted in 426 subjects assigned to three groups: control (n = 42); risk group (RG, n = 200), and MetS group (n = 184). Insulin sensitivity (IS) and cardiovascular risk were determined by the QUICKI and TG/HDL-C index, respectively. Serum GPx3 was determined by enzyme immunoassay and polymorphisms within GPX3 gene were identified by nucleotide sequencing. MetS group showed low IS and increased cardiovascular risk with respect to controls as well as higher GPx3 serum levels (172.9 ± 32.2 vs. 145.6 ± 24.8 ng/dL; p <0.05). Only three of the ten GPX3 SNPs screened were polymorphic with two haplotypes observed (CCT and TTA-rs8177404, rs8177406, and rs8177409), indicating tight linkage disequilibrium in this genetic region. No differences for either genotype or allele frequencies among groups were observed, but rs8177409 (allele T) was associated with cardiovascular risk (odds ratio [OR], 4.5; p = 0.0125). This study shows that serum levels of GPx3 are increased in subjects with MetS and that rs8177409 SNP was associated with cardiovascular risk in a Mexican population.

Impact of single nucleotide polymorphism in IL-4, IL-4R genes and systemic concentration of IL-4 on the incidence of glioma in Iraqi patients.

Glioma is the most common and believed to be one of the most aggressive tumors of the central nervous system (CNS) in humans. Very little information is available on the etiology and pathogenesis of these tumors to date. A significant gap remains in our current understanding of the molecular pathways involved in the genesis, progression and clinical behavior of these tumors. Recently, several single nucleotide polymorphisms (SNPs) have been identified in cytokine gene sequences, particularly within the promoter region of these genes, and have been shown to be associated with the development of different types of brain tumors. The present study investigates the association of C-33T SNP in the interleukin-4 (IL-4) gene with systemic IL-4 level and the S503P SNP in the IL-4R gene with the incidence of glioma.Blood samples were collected from 100 histologically confirmed adult patients with glioma, and 30 apparently healthy individuals from the same area. DNA was extracted from each blood sample, and the IL-4 and IL-4R genes were amplified using polymerase chain reaction (PCR) with gene-specific primers. Systemic IL-4 concentration was assessed in serum samples from each participant by enzyme-linked immunosorbent assay (ELISA). We observed a negative association between the homozygous genotype (CC) of the SNP C-33T of the IL-4 gene with the incidence of glioma (OR=0.19, 95% CI=0.035-1.02), while the T allele of the SNP demonstrated a significant protective association against glioma. Similarly, the heterozygous (CT) and homozygous mutant (CC) of the SNP S503P of the IL-4R gene demonstrated a significant association with glioma development (OR=0.405, 95% CI=0.17-0.969 and OR=0.147, 95% CI=0.036-0.6 respectively), while the C allele exhibited a highly significant association with protection from glioma formation.These findings suggest that the T allele of the SNP C-33T in the IL-4 gene and the C allele of the SNP S503P in IL-4R may have a protective role against glioma development.